The increased accumulation of cyclic AMP in cerebral cortical slices has provided evidence for the existence of denervation supersensitivity to NE, (norepinephrine) following treatment of rats with 6-hydroxydopamine, reserpine and surgical interruption of the NE pathway from the locus coeruleus. However, in the rat cortex slices both alpha-and beta-noradrenergic receptors appear to contribute to the increase in cyclic AMP in response to NE. Alpha-, but not beta-receptors appear to be involved in rewarded behavior. For this reason and also because guinea pig cortex contains only alpha-receptors, a study is proposed to examine the consequences of functional NE denervation in guinea pig cerebral cortex. Preliminary data show sensitization to adenosine following 2 days of high dose reserpine treatment. Cyclic AMP accumulation after exposure to 01. mM adenosine is increased by 100% after reserpine treatment and by 58% after .2 mM adenosine which is normally a maximal dose. Surprisingly, when NE was added to either dose of adenosine, no increased response was seen after reserpine, but DA (dopamine), .1 mM, produced a significant increase after reserpine with the low dose of adenosine. These data differ from those reported earlier in rat, but the earlier data might have contained an unrecognized contribution from endogenously released adenosine. This proposal will examine the reserpine effect on the dose-response relationship of adenosine to cyclic AMP accumulation. The 6-hydroxydopamine model will also be examined. The mechanism of the reserpine effect will be investigated by procedures capable of distinguishing between effect on blockade of uptake of adenosine, decreased destruction of cyclic AMP and increased syntheis of cyclic AMP. The impact of the reserpine effect on the response of the tissue to adenosine plus other neurohumoral agents will also be studied. DA-sensitive adenylyl cyclase in this tissue will be characterized by inhibitory constants derived from use of a battery of neuroleptic drugs. The results may be important for further understanding of the pathophysiology of schizophrenia.